Over the past 27 years, nearly 25 million people have died from AIDS. Available strategy such as highly active antiretroviral therapy (HAART) can prevent HIV transmission from parents to children but fail to treat this disease. The red alga Griffithia sp. has a novel antiHIV protein which is called Griffithsin (GRFT). The potent anti-viral activity of GRFT against both laboratory and primary isolates of HIV at picomolar concentrations makes this protein an attractive candidate microbiocide to prevent sexual transmission of HIV. At the first step, we optimized codon usage and designed hexa-histidine tagged GRFT (His-GRFT) sequence for expression in Escherichia coli. Then synthesized GRFT sequence was inserted in expressional vector pET28a (+) and transformed to E. coli BL21 strain. Finally, the recombinant production of GRFT was confirmed by SDS-PAGE. The expression system described in this work can provide a basis for the mass production of GRFT to allow further studies of the protein and investigation of therapeutic and preventive strategies against HIV.